tbuckley/cabot-search huggingface dataset:
Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies
Authors: Kim Kramer, Neeta Pandit-Taskar, Brian H. Kushner, Pat Zanzonico, John L. Humm, Ursula Tomlinson, Maria Donzelli, Suzanne L. Wolden, Sophia Haque, Ira Dunkel, Mark M. Souweidane, Jeffrey P. Greenfield, Satish Tickoo, Jason S. Lewis, Serge K. Lyashchenko, Jorge A. Carrasquillo, Bae Chu, Christopher Horan, Steven M. Larson, Nai-Kong V. Cheung, Shakeel Modak
Journal: Journal of Hematology & Oncology (2022)

Abstract Background The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. Patients and methods We conducted a phase I trial of intraventricular 131 I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients &gt; dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131 I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. Results Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma ( n = 16) and other B7H3-expressing solid tumors ( n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included &lt; grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. Conclusions cRIT with 131 I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. Trial registration : clinicaltrials.gov NCT00089245, August 5, 2004.
Temporary mechanical circulatory support devices: practical considerations for all stakeholders
Authors: Benjamin S. Salter, Caroline R. Gross, Menachem M. Weiner, Srinivas R. Dukkipati, Gregory W. Serrao, Noah Moss, Anelechi C. Anyanwu, Daniel Burkhoff, Anuradha Lala
Journal: Nature Reviews Cardiology (2022)
Kidney microbiota dysbiosis contributes to the development of hypertension
Authors: Xin-Yu Liu, Jing Li, Yamei Zhang, Luyun Fan, Yanli Xia, Yongyang Wu, Junru Chen, Xinyu Zhao, Qiannan Gao, Bing Xu, Chunlai Nie, Zhengyu Li, Aiping Tong, Wenjie Wang, Jun Cai
Journal: Gut Microbes (2022)

Gut microbiota dysbiosis promotes metabolic syndromes (e.g., hypertension); however, the patterns that drive hypertensive pathology and could be targeted for therapeutic intervention are unclear. We hypothesized that gut microbes might translocate to the kidney to trigger hypertension. We aimed to uncover their method of colonization, and thereby how to maintain blood pressure homeostasis. Using combined approaches based on fluorescence in situ hybridization (FISH) and immunofluorescence staining, electron microscopy analysis, bacterial cultures, species identification, and RNA-sequencing-based meta-transcriptomics, we first demonstrated the presence of bacteria within the kidney of spontaneously hypertensive rats (SHRs) and its normotensive counterpart, Wistar-Kyoto rats (WKYs), and patients with hypertension. Translocated renal bacteria were coated with secretory IgA (sIgA) or remained dormant in the L-form. Klebsiella pneumoniae (K.pn) was identified in the kidneys of germ-free (GF) mice following intestinal transplantation, which suggested an influx of gut bacteria into the kidneys. Renal bacterial taxa and their function are associated with hypertension. Hypertensive hosts showed increased richness in the pathobionts of their kidneys, which were partly derived from the gastrointestinal tract. We also demonstrated the indispensable role of bacterial IgA proteases in the translocation of live microbes. Furthermore, Tartary buckwheat dietary intervention reduced blood pressure and modulated the core renal flora-host ecosystem to near-normal states. Taken together, the unique patterns of viable and dormant bacteria in the kidney provide insight into the pathogenesis of non-communicable chronic diseases and cardiometabolic diseases (e.g., hypertension), and may lead to potential novel microbiota-targeted dietary therapies.
Integration of stool microbiota, proteome and amino acid profiles to discriminate patients with adenomas and colorectal cancer
Authors: Sofie Bosch, Animesh Acharjee, Mohammed Nabil Quraishi, Irene V Bijnsdorp, Patricia Rojas, Abdellatif Bakkali, Erwin EW Jansen, Pieter Stokkers, Johan Kuijvenhoven, Thang V Pham, Andrew D Beggs, Connie R Jimenez, Eduard A Struys, Georgios V Gkoutos, Tim GJ de Meij, Nanne KH de Boer
Journal: Gut Microbes (2022)

Background Screening for colorectal cancer (CRC) reduces its mortality but has limited sensitivity and specificity. Aims We aimed to explore potential biomarker panels for CRC and adenoma detection and to gain insight into the interaction between gut microbiota and human metabolism in the presence of these lesions.Methods This multicenter case-control cohort was performed between February 2016 and November 2019. Consecutive patients ≥18 years with a scheduled colonoscopy were asked to participate and divided into three age, gender, body-mass index and smoking status-matched subgroups: CRC (n = 12), adenomas (n = 21) and controls (n = 20). Participants collected fecal samples prior to bowel preparation on which proteome (LC-MS/MS), microbiota (16S rRNA profiling) and amino acid (HPLC) composition were assessed. Best predictive markers were combined to create diagnostic biomarker panels. Pearson correlation-based analysis on selected markers was performed to create networks of all platforms.Results Combining omics platforms provided new panels which outperformed hemoglobin in this cohort, currently used for screening (AUC 0.98, 0.95 and 0.87 for CRC vs controls, adenoma vs controls and CRC vs adenoma, respectively). Integration of data sets revealed markers associated with increased blood excretion, stress- and inflammatory responses and pointed toward downregulation of epithelial integrity.Conclusions Integrating fecal microbiota, proteome and amino acids platforms provides for new biomarker panels that may improve noninvasive screening for adenomas and CRC, and may subsequently lead to lower incidence and mortality of colon cancer.
Histone H3 proline 16 hydroxylation regulates mammalian gene expression
Authors: Xijuan Liu, Jun Wang, Joshua A. Boyer, Weida Gong, Shuai Zhao, Ling Xie, Qiong Wu, Cheng Zhang, Kanishk Jain, Yiran Guo, Javier Rodriguez, Mingjie Li, Hidetaka Uryu, Chengheng Liao, Lianxin Hu, Jin Zhou, Xiaobing Shi, Yi-Hsuan Tsai, Qin Yan, Weibo Luo, Xian Chen, Brian D. Strahl, Alex von Kriegsheim, Qi Zhang, Gang Greg Wang, Albert S. Baldwin, Qing Zhang
Journal: Nature Genetics (2022)
ROS-reactive PMS/PC drug delivery system improves new bone formation under diabetic conditions by promoting angiogenesis-osteogenesis coupling via down-regulating NOX2-ROS signalling axis
Authors: Zimei Wu, Qiaodan Hou, Tingting Chen, Xingzhu Jiang, Lulu Wang, Jing Xu, Lin Wang
Journal: Biomaterials (2022)
All the Tau We Cannot See
Authors: Bradley Hyman
Journal: Annual Review of Medicine (2022)

Alzheimer's disease (AD) was described in 1906 as a dementing disease marked by the presence of two types of fibrillar aggregates in the brain: neurofibrillary tangles and senile plaques. The process of aggregation and formation of the aggregates has been a major focus of investigation ever since the discoveries that the tau protein is the predominant protein in tangles and amyloid β is the predominant protein in plaques. The idea that smaller, oligomeric species of amyloid may also be bioactive has now been clearly established. This review examines the possibility that soluble, nonfibrillar, bioactive forms of tau—the “tau we cannot see”—comprise a dominant driver of neurodegeneration in AD.
Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling
Authors: Francisco Caiado, Larisa V. Kovtonyuk, Nagihan G. Gonullu, Jonas Fullin, Steffen Boettcher, Markus G. Manz
Journal: Blood (2022)

Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis, is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells in ≥4% of blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease, and all-cause mortality. Loss-of-function somatic mutations in TET2 are frequent drivers of CHIP. However, the contribution of aging-associated cooperating cell-extrinsic drivers, like inflammation, remains underexplored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ERT; Tet2+/flox; R26+/tm6[CAG-ZsGreen1]Hze) mouse models of Tet2+/-driven CHIP, we observed an association between increased Tet2+/- clonal expansion and higher BM levels of the inflammatory cytokine interleukin-1 (IL-1) upon aging. Administration of IL-1 to mice carrying CHIP led to an IL-1 receptor 1 (IL-1R1)-dependent expansion of Tet2+/- hematopoietic stem and progenitor cells (HSPCs) and mature blood cells. This expansion was caused by increased Tet2+/- HSPC cell cycle progression, increased multilineage differentiation, and higher repopulation capacity compared with their wild-type counterparts. In agreement, IL-1α-treated Tet2+/- hematopoietic stem cells showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α-mediated downregulation of self-renewal genes. More important, genetic deletion of IL-1R1 in Tet2+/- HPSCs or pharmacologic inhibition of IL-1 signaling impaired Tet2+/- clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2+/- CHIP progression during aging.
Integrating novel agents into the treatment of advanced mycosis fungoides and Sézary syndrome
Authors: Michael S. Khodadoust, Eric Mou, Youn H. Kim
Journal: Blood (2022)

Abstract Agents targeting the unique biology of mycosis fungoides and Sézary syndrome are quickly being incorporated into clinical management. With these new therapies, we are now capable of inducing more durable responses and even complete remissions in advanced disease, outcomes which were exceedingly rare with prior therapies. Yet, even this new generation of therapies typically produce objective responses in only a minority of patients. As our therapeutic options increase, we are now challenged with selecting treatments from a growing list of options. To gain the full benefit of these novel agents, we must develop strategies to match treatments for the patients most likely to benefit from them. Here, we consider both the current approaches to treatment selection based on clinical features and the future of molecular biomarker-guided therapy for patients with this heterogeneous disease.
A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer
Authors: Robert Jones, Ruth Plummer, Victor Moreno, Louise Carter, Desamparados Roda, Elena Garralda, Rebecca Kristeleit, Debashis Sarker, Tobias Arkenau, Patricia Roxburgh, Harriet S. Walter, Sarah Blagden, Alan Anthoney, Barbara J. Klencke, Mark M. Kowalski, Udai Banerji
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. Patients and Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. Results: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. Conclusions: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.
Retraction: ANGPTL1 Interacts with Integrin α1β1 to Suppress HCC Angiogenesis and Metastasis by Inhibiting JAK2/STAT3 Signaling
Authors: Qian Yan, Lingxi Jiang, Ming Liu, Dandan Yu, Yu Zhang, Yan Li, Shuo Fang, Yan Li, Ying-Hui Zhu, Yunfei Yuan, Xin Yuan Guan
Journal: Cancer Research (2022)

This article (1) has been retracted at the request of the editors.The two cell lines used throughout the study, QGY-7703 and LO2, have been reported to be misidentified (2, 3).
Ecological Speciation Promoted by Divergent Regulation of Functional Genes Within African Cichlid Fishes
Authors: Madeleine Carruthers, Duncan E Edgley, Andrew D Saxon, Nestory P Gabagambi, Asilatu Shechonge, Eric A Miska, Richard Durbin, Jon R Bridle, George F Turner, Martin J Genner
Journal: Molecular Biology and Evolution (2022)

Rapid ecological speciation along depth gradients has taken place repeatedly in freshwater fishes, yet molecular mechanisms facilitating such diversification are typically unclear. In Lake Masoko, an African crater lake, the cichlid Astatotilapia calliptera has diverged into shallow-littoral and deep-benthic ecomorphs with strikingly different jaw structures within the last 1,000 years. Using genome-wide transcriptome data, we explore two major regulatory transcriptional mechanisms, expression and splicing-QTL variants, and examine their contributions to differential gene expression underpinning functional phenotypes. We identified 7,550 genes with significant differential expression between ecomorphs, of which 5.4% were regulated by cis-regulatory expression QTLs, and 9.2% were regulated by cis-regulatory splicing QTLs. We also found strong signals of divergent selection on differentially expressed genes associated with craniofacial development. These results suggest that large-scale transcriptome modification plays an important role during early-stage speciation. We conclude that regulatory variants are important targets of selection driving ecologically relevant divergence in gene expression during adaptive diversification.
Hepatology Highlights
Authors: Bilal Asif, Vivian Ortiz, Caitlin B. Conboy, Luis Antonio Díaz, Juan Pablo Arab, Sumera I. Ilyas
Journal: Hepatology (2022)

Asif, Bilal; Ortiz, Vivian; Conboy, Caitlin B.; Díaz, Luis Antonio; Arab, Juan Pablo; Ilyas, Sumera I. Author Information
Marine omega-3 fatty acid supplementation and prevention of cardiovascular disease: update on the randomized trial evidence
Authors: Shari S Bassuk, JoAnn E Manson
Journal: Cardiovascular Research (2022)

Abstract To date, the VITamin D and OmegA-3 TriaL (VITAL) is the only large-scale randomized trial of marine omega-3 fatty acid (n−3 FA) supplementation for cardiovascular disease (CVD) prevention in a general population unselected for elevated cardiovascular risk. We review the findings of VITAL, as well as results from recent secondary prevention trials and updated meta-analyses of n−3 FA trials in the primary and secondary prevention of CVD. In VITAL, a nationwide sample of 25 871 US adults aged 50 and older, including 5106 African Americans, were randomized in a 2 × 2 factorial design to n−3 FAs (1 g/day; 1.2:1 ratio of eicosapentaenoic to docosahexaenoic acid) and vitamin D3 (2000 IU/day) for a median of 5.3 years. Compared with an olive oil placebo, the n−3 FA intervention did not significantly reduce the primary endpoint of major CVD events [composite of myocardial infarction (MI), stroke, and CVD mortality; hazard ratio (HR) = 0.92 (95% confidence interval 0.80–1.06)] but did significantly reduce total MI [HR = 0.72 (0.59–0.90)], percutaneous coronary intervention [HR = 0.78 (0.63–0.95)], fatal MI [HR = 0.50 (0.26–0.97)], and recurrent (but not first) hospitalization for heart failure [HR = 0.86 (0.74–0.998)]. The intervention neither decreased nor increased risk of atrial fibrillation. African Americans derived the greatest treatment benefit for MI and for recurrent hospitalization for heart failure (P interaction &amp;lt; 0.05 for both outcomes). Meta-analyses that include VITAL and high-risk or secondary prevention n−3 FA trials show coronary, but generally not stroke, risk reduction. More research is needed to determine which individuals may be most likely to derive net benefit. (VITAL clinicaltrials.gov identifier: NCT01169259).
Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: a phase 2, randomised, double-blind, placebo-controlled trial
Authors: Amanda Vrselja, Ardian Latifi, Rodney J Baber, Bronwyn G A Stuckey, Michael G Walker, Vered Stearns, Martha Hickey, Susan R Davis
Journal: The Lancet (2022)
Removal of an over-the-scope clip using the over-the-scope clip-removal system before performing polypectomy of the recurrent polyp
Authors: Jorge Pérez, Francisco Garrido, María Dolorez Pérez, Jose Carlos Villa, Angel Ponferrada, Alvaro Martínez-Alcalá
Journal: Endoscopy (2022)

We present the case of a 64-year-old woman with no significant past medical history who was found during a screening colonoscopy to have a 45-mm sessile polyp at the hepatic angle. The initial resection attempt was complicated by massive spurting bleeding, which was controlled by adrenaline injection and the application of eight hemoclips. During the next colonoscopy, we observed adenomatous tissue with significant fibrosis and decided to perform endoscopic full-thickness resection (EFTR) with a "close and cut" technique using a 14/6 t over-the-scope (OTS) clip (Ovesco Endoscopy AG, Tübingen, Germany) [1] [2]. This resection was performed without any complications and the patient was discharged after 24 hours.
The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health
Authors: Kale S. Bongers, Rishi Chanderraj, Robert J. Woods, Roderick A. McDonald, Mark D. Adame, Nicole R. Falkowski, Christopher A. Brown, Jennifer M. Baker, Katherine M. Winner, Daniel J. Fergle, Kevin J. Hinkle, Alexandra K. Standke, Kimberly C. Vendrov, Vincent B. Young, Kathleen A. Stringer, Michael W. Sjoding, Robert P. Dickson
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown. Objectives: To establish and interrogate the role of the gut microbiome in calibrating body temperature. Methods: We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal LPS in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals. Measurements and Main Results: Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that the composition of patients’ gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures compared with control animals. The Lachnospiraceae family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice. Conclusions: The gut microbiome is a key modulator of body temperature variation in both health and critical illness and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.
Truncal Dynamics May Trump: Serial ctDNA to Predict Early Therapeutic Response
Authors: Madhulika Eluri, Scott Kopetz, Christine M. Parseghian
Journal: Clinical Cancer Research (2022)

Summary Promising utility of using serial ctDNA in metastatic colorectal cancer to both refine patient selection, reduce toxicity due to chemotherapy, and to evaluate emerging resistance mechanisms may lead the way to novel therapeutic strategies. However, important questions remain in validating its use as a predictive biomarker of treatment response. See related article by Vidal et al., p. 379
Real-time retrieval and repositioning of a lumen-apposing metal stent maldeployed in the pancreatic fluid collection
Authors: Jingyuan Xiang, Enqiang Linghu, Ningli Chai
Journal: Endoscopy (2022)

The lumen-apposing metal stent (LAMS) has been reported to be a useful device for pancreatic fluid collection (PFC) [1]. The technical success rates are generally high, but accidental deployment of a stent flange might happen occasionally. This is a case of a real-time salvage of a maldeployed LAMS in PFC drainage ([Video 1]).
Clinical feasibility of endoscopic full-thickness resection and closure using O-ring and over-the-scope clip system
Authors: Takehiro Iwasaki, Kunihisa Uchita, Nobuya Kobayashi, Koji Kojima, Noriko Nishiyama, Hiromichi Yamai, Hideki Kobara
Journal: Endoscopy (2022)

Endoscopic full-thickness resection (EFTR) has been developed to treat gastrointestinal stromal tumors (GISTs) of < 3 cm [1]. The challenges were to secure the surgical field and to establish a reliable endoscopic closure method [2]. Therefore, we have developed a novel strategy of traction-assisted EFTR followed by O-ring band [3] and over-the-scope clip closure through an animal study [4]. We describe a clinical case in which this strategy was feasible ([Video 1]).